The broad objective of this program is to perform preclinical experimentation on animal models of myocardial ischemia and subsequent chronic heart failure (HF) to elucidate the mechanisms of their development and to evaluate the potential of different therapeutic modalities including gene therapy with angiogenic growth factors and stem cells implantation. In keeping with a broad objective of the program we mustered the techniques for in vivo assessment of cardiac function in rats and mice - the high resolution Doppler-Echocardiography and pressure/volume loop analysis with intracardiac pressure-conductance catheter. Using this "cutting edge" technology we are conducting extensive functional and dynamic characterization of chronic HF which is developing subsequently to ligation of a coronary artery in mice and rats. This experimental model is used for testing the different treatment modalities of HF and for transgenic-based studies of the role of different receptors pathways in development of heart failure. Using the experimental model of myocardial infarction (MI) in mice we identified and characterized previously overlooked phenotype of chronic HF associated with small, non-transmural infarction. This phenotype was not accompanied by left ventricular enlargement and was characterized by increased ventricular elastance in end-systole and stiffness in end- diastole, i.e., it might represent a diastolic model of heart failure. Increased ventricular elastance in this phenotype matched the increased arterial elastance so that ventricular-arterial coupling remains preserved. In longitudinal study we showed that development of this non-dilated phenotype was independent from usually described dilated phenotype characterized by reduced ventricular elastance. The role of beta-adrenerging receptors (AR) signaling in development of HF is clearly important but purely understood. It is widely accepted now that beta-1 AR activation is associated with development of HF, thus, the use of beta-1 AR antagonists became a recommended therapy for HF. The possible role of beta-2 AR agonists remains debatable, however the consensus is that similarly to beta-1 AR, activation of beta-2 AR during HF is harmful. Recent research in LCS using single myocytes indicated that beta-2 AR agonist, fenoterol, possesses a unique ability to activate Gs, but not Gi pathways. Capitalizing on this finding we studied the effects of chronic treatment with fenoterol in rats starting 2 weeks after ligation of a coronary artery. Our results indicated that similarly with the effect of beta-1 AR antagonists, the chronic treatment with fenoterol significantly attenuates the development of HF. It results in a reduction of MI size, reduction of LV remodeling, and it actually prevents the functional decline of cardiac function in rats. Erythropoietin (EPO), natural stimulant of erythropoiesis, recently emerged as potential antiapoptotic and angiogenic factor. We tested the hypothesis that single treatment with EPO will reduce the cardiac damage induced by coronary ligation and subsequent decline of cardiac function. In recently completed experiments in rats we showed that single intraperitoneal injection of recombinant human EPO (3000 IU/kg) immediately after ligation of the coronary artery results in 50% reduction of myocardial infarction eight weeks later. During eight weeks after induction of myocardial infarction, left ventricular remodeling and function decline in EPO treated rats was significantly attenuated and statistically not different from that in sham operated animals. Twenty four hours after ligation of coronary artery the amount of apoptotic myocytes measured in the myocardial risk area (area immediately adjacent to the infarct site) was reduced in half in the EPO treated rats in comparison to untreated animals.